Infection and inflammation remain a significant contributor to pregnancy loss and infant morbidity and mortality. Maternal infections during pregnancy represent a significant risk factor for adverse neurobehavioral outcomes, including cognitive delay, schizophrenia, autism and mental retardation. Common organisms that infect pregnant women include E. coli, Group B streptococcus, Mycoplasma and Ureaplamsa; all of these pathogens are implicated in perinatal injury and exposure to these organisms has been associated with long term consequences for the offspring. These particular organisms are most likely to contribute to perinatal morbidity through colonization and/or infection in the uterine cavity not from systemic infection of the mother. Understanding this more common clinical scenario, we have developed mouse models that accurately mimic intrauterine infection and inflammation in the human. Research from our laboratory has demonstrated that exposure to intrauterine infection results in both fetal and postnatal brain injury. More recently, we have demonstrated that even with a low dose model of intrauterine inflammation-in which there is minimal immune response in the uterus-that bacterial by-products in the uterine cavity can cause fetal and postnatal brain injury. While activation of the immune response in both the mother and feto-placental unit is believed to play a crucial role in the pathogenesis of fetal brai injury from prenatal infection, the necessity of Toll-like receptor (TLR) signaling pathways in the mother, placenta and/or fetus to inflammation-induced fetal brain injury has not been elucidated. Until the innate immune pathways mechanistically responsible for adverse outcomes from prenatal infection are revealed, therapeutic strategies cannot begin. Targeting maternal TLR pathways may be an important therapeutic strategy to prevent adverse outcomes; however, this approach may be for naught if pathogen or pathogen by-products can directly activate fetal TLR in the absence of a maternal immune response and TLR therapies do not reach the fetal compartment. Moreover, if immune mediators activate non- TLR pathways, in either the mother or fetus, targeting TLR signaling would fail to prevent outcomes. It remains unknown whether maternal and/or fetal TLR signaling is a crucial step in brain injury from exposure to prenatal inflammation; as such, directive therapies to these pathways have not been pursued. We hypothesize 1) that fetal brain injury from prenatal infection occurs by a common pathway regardless of the initiating bacterial pathogen and/or the specific TLR that is activated; 2) maternal TLR signaling is sufficient, but not necessary, for inflammation-induced brain injury, and 3) that fetal (and placenta) TLR signaling is sufficient for inflammation-induced fetal brain injury. Using genetically manipulated mice in the TLR pathway and embryo transfer technique, we will create pregnant dams in which the mother and feto-placental unit are divergent genoyptes. Thus, with our mouse model of intrauterine infection and delineated outcomes, we will be able to determine the role of maternal vs. fetal TLR signaling in adverse outcomes after exposure to prenatal infection.